Process for preparation of 1,4-benzodioxane derivative

ABSTRACT

A novel process for preparing a 1,4 benzodioxane derivative shown by the formula (1) which is a useful intermediate of circulatory drugs and drugs for psychoneurosis, characterized in sulfonating a phenoxypropanediol with a sulfonyl halide, eliminating the protective group, and then cyclizing the sulfonated compound by treating with a base followed by, if necessary, further sulfonation. ##STR1## In the above formula, R 1  is H, RSO 2 , R is alkyl, phenyl which may be substituted with alkyl, R 2 , R 3 , R 4  are H, halogen, OH, nitro, cyano, formyl, COOH, alkoxycarbonyloxy, alkyl, alkoxy, haloalkyl, N,N-dialkylamino, alkylcarbonyl, alkoxycarbonyl, phenyl which may be substituted by alkyl, etc.22

FIELD OF ART

The present invention relates to a process for the preparation of a1,4-benzodioxane derivative useful for the intermediate of circulatorydrugs and drugs for psychoneurosis which are alpha and beta-adrenergicantagonists.

BACKGROUND OF ART

A 1,4-benzodioxane derivative is used for an intermediate for thepreparation of circulatory drugs and drugs for psychoneurosis havingalpha and beta-adrenergic antagonist-activity and its various kind ofprocesses are known. For example, a method of reacting a catecholderivative with glycidyl tosylate in the presence of sodium hydride(Japanese patent publication No.9613/1994) or a method of reacting acatechol derivative with epichlorohydrin in the presence of pyridine (J.Org. Chem. 46,3846 (1981)) is known. A method is also known to make a1,4-benzodioxane skeleton by reactng a catechol derivative with glycerol1-tosylate acetonide and, after removing the protective group, theacetonide, by introducing two tosyl groups onto it and then by isolatingit, and further by cyclizing it (J. Chem. Soc., Chem. Commun., 921(1976)).

Among the above methods, besides the method comprising the use ofglycidyl tosylate is costly because of expense of that compound, theepoxy group is also reduced on the deprotection by hydrogenolysis andthe yield decreases. In the method comprising the use ofepichlorohydrin, the excess of epichlorohydrin and dichloropropanediolas a by-product must be eliminated by their evaporation with xylene, andthe hydrochloric acid and acetic acid used must be eliminated byevaporation with ethanol, and therefore such procedures are troublesome.Moreover, the reaction is carried out under reflux of piperidine orhydrochloric acid. Therefore a compound having substituents which areunstable to an acid or a base can not be used. When using a opticallyactive epichlorohydrin, racemization occurs and an optically pureproduct cannot be obtained. In the method which comprises the reactionof a catechol derivative with glycerol 1-tosylate acetonide, theresulting ditosylated product must be separated after tosylation andtherefore the yield of the ditosylated product is 55%, or lower. Thesemethods have many disadvantages in application of an industrial scale.An improved method has been desired.

DISCLOSURE OF INVENTION

The present inventors, taking into consideration the above fact,extensively engaged in study to find an improved method for thepreparation of a 1,4-benzodioxane derivative, and found the presentinvention. After sulfonating a phenoxypropanediol compound, by cyclizingthe resulting product in the presence of a base, the desired1,4-benzodioxane derivative is favorably obtained in an industrialscale.

The present invention relates to a process of preparing a1,4-benzodioxane derivative as shown by the following formula (1)##STR2## wherein R¹ is a hydrogen atom or RSO₂ in which R is C₁ -C₄alkyl, or phenyl which may be substituted by C₁ -C₄ alkyl, R², R³ and R⁴are, respectively, hydrogen, halogen, hydroxy, nitro, cyano, formyl,carboxyl, alkoxycarbonyloxy having 1-4 carbon atoms in the alkylportion, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₁ -C₄ haloalkyl, N,N-di C₁ -C₄alkylamino, alkylcarbonyl having 1-4 carbon atoms in the alkyl portion,alkoxycarbonyl having 1-4 carbon atoms in the alkyl portion or phenylwhich may be substituted by C₁ -C₄ alkyl, or two groups among R², R³,and R⁴ may be combined together to constitute methylenedioxy on adjacentcarbon atoms, or two groups among R², R³ and R⁴ may be combined togetherto constitute phenyl on the adjacent carbon atoms, which ischaracterized in reacting a diol compound as shown by the followingformula (2) ##STR3## wherein R², R³ and R⁴ are the same as definedabove, R⁵ is benzyl, allyl (e.g. 2-propenyl, etc.), o-nitrobenzyl,t-butyldimethylsilyl or benzyloxycarbonyl, or R⁵ may be constitutedmethylenedioxy, isopropylidenedioxy, cyclohexylidenedioxy ordiphenylmethylenedioxy together with oxygen atom in the hydroxy or theR⁵ O-group, provided that when any one of R², R³ and R⁴ is hydroxy andthe hydroxy is bound on the carbon atom adjacent to the carbon atomsubstituted by R⁵ O-group, with a sulfonyl halide in the presence of abase to give a sulfonated compound(s) as shown in the following formulae(3) and/or (4) ##STR4## wherein R, R¹, R², R³, R⁴ and R⁵ are the same asdefined above, and after the elimination of the protective group R⁵ ofthe sulfonated compound, cyclizing the compound by treating with a base.

BEST MODE OF PRESENT INVENTION

The present invention is described in detail as shown in the followingreaction scheme. ##STR5## wherein R, R², R³, R⁴ and R⁵ are the same asdefined above.

First, a diol compound (2) is reacted with a sulfonyl halide forexample, an arylsulfonyl halide, such as benzenesulfonyl chloride,toluenesulfonyl chloride, etc. or C₁ -C₄ alkylsulfonyl halide, such asmethanesulfonyl chloride, etc., in the presence of a base to give amonosulfonated compound (3) or a disulfonated compound (4) or a mixtureof both compounds. As a base, an organic base, such as triethylamine,pyridine, etc., is used. This reaction is carried out in the absence ofa solvent or in the presence of a solvent, for example, an ether, suchas tetrahydrofuran, dioxane, t-butylmethyl ether, diethyl ether, etc., achlorinated compound, such as methylene chloride, chloroform,dichloroethane, etc.; or an aromatic hydrocarbon, such as benzene,toluene, etc. The reaction temperature is 0°-100° C., preferably 10°-50°C. This reaction proceeds in the absence of a catalyst, and the reactionis accelerated by using N,N-dimethylaminopyridine, etc., as a catalyst,and the yield is improved. When a mixture of a monosulfonated compound(3) and a disulfonated compound (4) is produced, the mixture can beseparated by liquid column chromatography, etc. But the mixture may beused without separation in the next step.

Next, the elimination of the protective group R⁵ on the sulfonatedcompound (3) or (4) is carried out. When the protective group R⁵ isbenzyl, allyl or benzyloxycarbonyl, the protective group is deprotectedby being subjected to catalytic hydrogenation with palladium-carbon atroom temperature in an organic solvent, such as methanol, ethanol, ethylacetate, etc. When an o-nitrobenzyl is used as a protective group, thegroup is eliminated by radiation on it in an organic solvent, such asmethanol, ethanol, etc. When the protective group R⁵ ist-butyldimethylsilyl, the protective group is removed by using a salt ofa fluoro compound, such as sodium fluoride, potassium fluoride ortetrabutylammonium fluoride in an organic solvent, such asN,N-dimetylformamide, tetrahydrofuran, etc., or a mixture of the organicsolvent and water. When the protective group R⁵ is methylenedioxy,isopropylidenedioxy, cyclohexylidenedioxy or diphenylmethylenedioxy, theprotective group is eliminated under acidic conditions usually used inthe deprotection of such a protective group.

A compound (5), a compound (6) or a mixture of them thus obtained iscyclized by treating it with a base to produce a desired1,4-benzodioxane derivative (1A) (R¹ ═H) and/or (1B) (R¹ ═RSO₂).Examples of the solvent are a dipolar aprotic solvent, such asN,N-dimethylformamide, dimethyl sulfoxide, sulfolane,hexamethylphosphoramide, etc.; an ether, such as tetrahydrofuran,dioxane, t-butylmethyl ether, diethyl ether, etc.; a chlorinatedcompound, such as methylene chloride, chloroform, dichloroethane, etc.;an alcohol, such as methanol, ethanol, isopropanol, t-butanol, etc.;water, and so on.

Examples of the base are an alkali metal hydride, an alkali metalhydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate,an alkaline earth metal carbonate, an alkali metal salt of C₁ -C₄alkanol, or tri C₁ -C₄ alkylamine. Sodium hydride, sodium hydroxide,potassium hydroxide, calcium hydroxide, sodium carbonate, potassiumcarbonate, sodium methoxide, sodium ethoxide, triethylamine andethyldiisopropylamine are illustrated. The amount of the base is 1-5mol, preferably 1-3 mol per compound (5) or (6). The reactiontemperature is -20°-80° C., preferably 0°-50° C. It is thought that onthe cyclization of a compound (5), an epoxide is produced and then theepoxide reacts with a hydroxy on the benzene ring to give the cyclizedcompound. In this reaction there is a possibility to produce a 6membered ring and a 7 membered ring, but the 6 membered ring ispreferentially produced.

A 1,4-benzodioxane derivative (1A) (R¹ ═H) thus prepared, is reactedwith an arylsulfonyl halide, such as benzenesulfonyl chloride,toluenesulfonylchloride, etc.; or a C₁ -C₄ alkylsulfonyl halide, such asmethanesulfonyl chloride, etc., in the presence of a base to produce a1,4-benzodioxane derivative (1B) (R¹ is RSO₂, R is C₁ -C₄ alkyl, phenylwhich may be substituted by C₁ -C₄ alkyl). When a mixture of a compound(5) and a compound (6) is cyclized, a mixture of a 1,4-benzodioxanederivative (1) wherein R¹ is H, and a 1,4-benzodioxane derivative (1)wherein R¹ is RSO₂, is obtained, but this mixture is subjected to thenext reaction with an arylsulfonyl halide or a C₁ -C₄ alkylsulfonylhalide in the same method as mentioned above to give only a compoundwherein R¹ is RSO₂.

A diol compound (2), a starting material of the present invention, issynthesized according to the reaction scheme as mentioned below.##STR6## wherein R², R³, R⁴ and R⁵ are the same as defined above.

That is, a catechol derivative (7) is reacted with3-chloro-1,2-propanediol (8) in the presence of a base in a solvent toproduce a diol compound (2). The solvent is a dipolar aprotic solvent,such as N,N-dimethylformamide, dimethyl sulfoxide, sulfolane,hexamethylphosphoramide, etc.; an ether, such as tetrahhdrofuran,dioxane, t-butylmethyl ether, diethyl ether, etc.; a chlorinatedcompound, such as methylene chloride, chloroform, dichloroethane, etc.;an alcohol, such as methanol, ethanol, isopropanol, t-butanol, etc.;water, and so on.

Examples of the base are an alkali metal hydride, an alkali metalhydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate,an alkaline earth metal carbonate, an alkali metal salt of C₁ -C₄alkanol, or tri C₁ -C₄ alkylamine. Sodium hydride, sodium hydroxide,potassium hydroxide, calcium hydroxide, sodium carbonate, potassiumcarbonate, sodium methoxide, sodium ethoxide, triethylamine andethyldiisopropylamine are illustrated. Sodium hydride, sodium methoxideor sodium ethoxide is preferably used, and sodium hydride among them ismore preferably used. The amount of the base is 1-4 mol, preferably1.1-2.5 mol per compound (7). The reaction temperature is -20°-150° C.,preferably 20°-100° C. When the reaction temperature is too low, thereaction rate decreases and that is not practical. On the other hand,when the temperature is too high, a glycidol produced during thereaction may be polymerized and the yield is significantly reduced.

A diol compound (2), a starting material, used in the present invention,may be prepared by the known method, that is by reacting a catecholderivative (7) with glycidol. Glycidol is unstable and is readilypolymerized, but 3-chloro-1,2-propanediol (8) is stable and notexpensive and the method consisting of the use of this compound (8) asmentioned above, therefore, is beneficial in the industrial scale.

Also, by using an optically active diol compound (2), an opticallyactive 1,4-benzodioxane derivative is prepared. Such an optically activediol compound (2) is prepared, for instance, by reacting a catecholderivative (7) with optically active 3-chloro-1,2-propanediol under thesame conditions mentioned above. When 3-chloro-1,2-propanediol havinghigh optical purity is used as a starting material, the racemization isnot markedly occurred during the reaction and therefore, a1,4-benzodioxane derivative is obtainable in the high optical purity.3-Chloro-1,2-propanediol having the high optical purity (more than 98%ee), for example, is obtained by using the method described in Japanesepatent publication No.73998/1992 or No.73999/1992 developed by thepresent applicant. According to the process of the present invention, a(S)-1,4-benzodioxane derivative is obtained from(R)-3-chloro-1,2-propanediol, and a (R) -1,4-benzodioxane derivative isobtained from (S)-3-chloro-1,2-propanediol.

The present invention is in detail explained in the following Examples,but the invention is not limited to the examples.

EXAMPLE 1

(i) Preparation of a Diol Compound

Sodium hydride (2.07 g, 0.05 mol in oil (60% w/w)) was washed withn-hexane, and anhydrous N,N-dimethylformamide (15 ml) was added to it.To the suspension was dropped 2-benzyloxyphenol (6 g, 0.03 mol) inanhydrous N,N-dimethylformamide (10 ml) under ice cooling in over a 10minute period. After the emission of gas was over, to the solution wasdropped monochlorohydrin (3.98 g, 0.036 mol) in anhydrousN,N-dimethylformamide (5 ml) under ice cooling. The solution was stirredfor 3 hours at 60° C. After the reaction was completed, to the reactionmixture was added a saturated aqueous solution of ammonium chloride (500ml) and the mixture was extracted with ethyl acetate, and the ethylacetate phase was washed with saturated brine and water, dried overanhydrous magnesium sulfate and concentrated in vacuo to give a crudeproduct as a pale yellow oil. The crude product was purified with columnchromatography (silica gel, n-hexane/ethyl acetate (6:1)) to give3-(2-benzyloxy)phenoxy-1,2-propanediol (7.88 g) as a colorless oil.

(ii) Preparation of a Compound (3) and a Compound (4)

The diol compound (7.88 g, 0.029 mol) obtained above (i) was dissolvedin pyridine (10 ml) and to the solution was added p-toluenesulfonylchloride (12.16 g, 0.064 mol) under ice cooling and then the mixture wasstirred at room temperature for 12 hours. After the reaction was over,to the reaction mixture was added a 3% aqueous solution of hydrochloricacid (300 ml) and the mixture was extracted with ethyl acetate. Theethyl acetate phase was washed twice with water, dried over anhydrousmagnesium sulfate and concentrated in vacuo to give 15.2 g of a mixtureof a ditosylated compound and a monotosylated compound (ratio,6:1) as apale yellow oil.

(iii) Preparation of a Compound (5) and a Compound (6)

In a mixture of ethanol (600 ml) and ethyl acetate (100 ml) wasdissolved 15.2 g of a mixture of a ditosylated compound and amonosylated compound prepared above (ii) and the solution was subjectedto hydrogenation under hydrogen in the presence of 10% palladium oncarbon (1 g). After the reaction was finished, palladium/carbon wasfiltered off and the filtrate was concentrated in vacuo to give 12.9 gof a mixture of 1,2-ditosylated 3-(2-hydroxyphenoxy)-1,2-propanediol and1-monotosylated 3-(2-hydroxyphenoxy)-1,2-propanediol.

(iv) Preparation of a 2,3-Dihydro-1,4-Benzodioxane Derivative

Sodium hydride (1.59 g, 0.04 mol in oil (60% w/w)) was washed withn-hexane and to it was added 10 ml of anhydrous N,N-dimethylformamide.To the suspension was added 12.9 g of a mixture of a 1,2-ditosylatedcompound and a 1-tosylated compound prepared above (iii) in anhydrousN,N-dimethylformamide (100 ml) under an atmosphere of nitrogen under icecooling in over a 10 minute period and then the mixture was stirred for3 hours at room temperature. To the solution was added a saturatedaqueous solution of ammonium chloride and the solution was extractedwith ethyl acetate. The ethyl acetate phase was washed with saturatedbrine and water, dried over anhydrous magnesium sulfate and concentratedin vacuo to give 7.5 g of a crude mixture of2-tosyloxymethyl-1,4-benzodioxane and 2-hydroxymethyl-1,4-benzodioxaneas a oil. The mixture might be purified with column chromatography(silica gel, n-hexane/ethyl acetate (3:2)), but the mixture was used forthe next step without purification.

To 7.5 g of the mixture of 2-tosyloxymethyl-1,4-benzodioxane and2-hydroxymethyl-1,4-benzodioxane in dichloromethane (15 ml) and pyridine(3.16 g, 0.04 mol) was added p-toluenesulfonyl chloride (0.76 g, 0.04mol) under ice cooling and the mixture was stirred at room temperaturefor 12 hours. After the completion of the reaction, a 3% aqueoussolution of hydrochloric acid (200 ml) was added to the reaction mixtureand the reaction mixture was extracted with ethyl acetate and the ethylacetate phase was washed twice with water, dried over anhydrousmagnesium sulfate, and concentrated in vacuo to give a crude product asa oil. The crude product was purified with column chromatography (silicagel, n-hexane/ethyl acetate (3:1)) to give 7.89 g of2-tosyloxymethyl-1,4-benzodioxane (yield 83% : based on2-benzyloxyphenol).

EXAMPLE 2

By using 2-benzyloxy-3-methylphenol (6.43 g) instead of2-benzyloxyphenol and by using optically active (R)-monochlorohydrin(optical purity:99.0% ee), according to the method of example 1 therewas obtained (S)-2-tosyloxymethyl-8-methyl-1,4-benzodioxane (8.02 g,yield 80%). During the reaction the optical purity of(S)-2-hydroxymethyl-8-methyl-1,4-benzodioxane was 97.4% ee by themeasurement with the chiral column OD (Daisel Chemical Industries Ltd.)

EXAMPLE 3

By using 2-benzyloxy-4,5-methylenedioxyphenol (7.33 g) instead of2-benzyloxyphenol in the same method described in Example 1, there wasobtained 2-tosyloxymethyl-6,7-methylenedioxy-1,4-benzodioxane (8.5 g,yield 78%).

EXAMPLE 4

By using 2-benzyloxy-3-methoxyphenol (6.91 g) instead of2-benzyloxyphenol in the same method described in Example 1, there wasobtained 2-tosyloxymethyl-8-methoxy-1,4-benzodioxane (8.51 g, yield81%).

EXAMPLE 5

By using 2-benzyloxy-6-fluorophenol (6.55 g) instead of2-benzyloxyphenol in the same method described in Example 1, there wasobtained 2-tosyloxymethyl-5-fluoro-1,4-benzodioxane (7.04 g, yield 69%).

EXAMPLE 6

By using 2-benzyloxy-5-nitrophenol (7.36 g) instead of 2-benzyloxyphenolin the same method described in Example 1, there was obtained2-tosyloxymethyl-6-nitro-1,4-benzodioxane (7.92 g, yield 72%).

EXAMPLE 7

By using 2-benzyloxy-5-ethoxycarbonylphenol (8.17 g) instead of2-benzyloxyphenol in the same method described in Example 1, there wasobtained 2-tosyloxymethyl-7-ethoxycarbonyl-1,4-benzodioxane (8.85 g,yield 75%).

EXAMPLE 8

On the occasion of the preparation of2-tosyloxymethyl-8-hydroxy-1,4-benzodioxane, by using4-hydroxy-2,2-dimethyl-1,3-benzo d!dioxole (4.98 g) instead of2-benzyloxyphenol, the objective compound was obtained, according to themethod described in Example 1, provided that, intermediates (5) and (6)wherein R is p-CH₃ C₆ H₄, R² is 3-OH, R³ and R⁴ are H, were prepared asthe following procedure.

A mixture (14.3 g) of a compound (3) and a compound (4) wherein R isp-CH₃ C₆ H₄, R² and R5 are -OC(CH₃)₂ -, R³ and R⁴ are hydrogen, wasrefluxed in 6N hydrochloric acid for 4 hours. After the reaction wasover, to the mixture is added methylene chloride and the methylenechloride phase was washed with a saturated aqueous solution of sodiumhydrogen carbonate and water, dried over anhydrous magnesium sulfate andconcentrated in vacuo to give 11.8 g of a mixture of a compound (5) anda compound (6).

This mixture was treated in the same method described in Example 1 togive the objective compound (6.55 g, yield 65%).

EFFECT OF INVENTION

According to the present invention, a 1,4-benzodioxane derivative isprepared in the high yield and by the convenient procedures in theindustrial scale without the isolation of the intermediate producedduring the reaction, by using a diol compound which is synthesized froma catechol derivative. Especially, it is economical to prepare a diolcompound by reacting a catechol derivative with3-chloro-1,2-propanediol. And in this reaction, by using an opticallyactive 3-chloro-1,2-propanediol, a 1,4-benzodioxane of high opticalpurity is obtainable without marked racemizaion during the reaction.

We claim:
 1. A process for preparing a 1,4-benzodioxane derivative asshown by the following formula (1) ##STR7## wherein R¹ is hydrogen atomor RSO₂ in which R is C₁ -C₄ alkyl, or phenyl which may be substitutedby C₁ -C₄ alkyl, R², R³ and R⁴ are respectively hydrogen, halogen,hydroxy, nitro, cyano, formyl, carboxyl, alkoxycarbonyloxy having 1-4carbon atoms in the alkyl portion, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₁ -C₄haloalkyl, N,N-di C₁ -C₄ alkylamino, alkylcarbonyl having 1-4 carbonatoms in the alkyl portion, alkoxycarbonyl having 1-4 carbon atoms inthe alkyl portion or phenyl which may be substituted by C₁ -C₄ alkyl, ortwo groups among R², R³, and R⁴ may be combined together to constitutemethylenedioxy on adjacent carbon atoms, or two groups among R², R³ andR⁴ may be combined together to constitute phenyl on adjacent carbonatoms, wherein a diol compound as shown by the following formula (2)##STR8## wherein R², R³ and R⁴ are same as defined above, R⁵ is benzyl,allyl, o-nitrobenzyl, t-butyldimethylsilyl or benzyloxycarbonyl, or R⁵may be constituted methylenedioxy, isopropylidenedioxy,cyclohexylidenedioxy or diphenylmethylenedioxy together with oxygen atomin the hydroxy or the R⁵ O-group, provided that when any one of R², R³and R⁴ is hydroxy and the hydroxy is bound on the carbon atom adjacentto the carbon atom substituted by R⁵ O-group, is reacted with a sulfonylhalide in the presence of a base to obtain a sulfonated compound asshown by the following formulae (3) and/or (4) ##STR9## wherein R, R¹,R², R³, R⁴, and R⁵ are the same as defined above, and after eliminationof the protective group R⁵ of the sulfonated compound, the compound iscyclized by treating with a base.
 2. The process for preparing a1,4-benzodioxane derivative claimed in claim 1 wherein, after theelimination of the protective group on a mixture of a compound shown bythe formula (3) and a compound shown by the formula (4), the deprotectedcompound is subjected to cyclization under a base, and the cyclizedcompound shown by the formula (1) is further reacted with a sulfonylhalide.
 3. The process for preparing a 1,4-benzodioxane derivativeclaimed in claim 1 wherein an optically active 1,4-benzodioxanederivative is prepared by using an optically active diol shown informula (2).
 4. The process for preparing a 1,4-benzodioxane derivativeclaimed in claim 1 wherein the sulfonyl halide is toluenesulfonylchloride or C¹ -C⁴ alkyl sulfonyl chloride.
 5. The process for preparinga 1,4-benzodioxane derivative claimed in claim 4 wherein the sulfonylhalide is toluenesulfonyl chloride.
 6. The process for preparing a1,4-benzodioxane derivative claimed in claim 1 in which the protectivegroup R⁵ , wherein R⁵ is benzyl, allyl or benzyloxycarbonyl, on thesulfonated compound shown by formula (3) or (4) is eliminated underhydrogenation with palladium/carbon in an organic solvent.
 7. Theprocess for preparing a 1,4-benzodioxane derivative claimed in claim 1wherein a catechol derivative shown by the following formula (7)##STR10## wherein R₂, R³, R⁴ and R⁵ are the same defined in claim 1, isreacted with 3-chloro-1,2-propanediol shown by the following formula (8)##STR11## in the presence of a base to obtain a diol compound shown bythe formula (2).
 8. The process for preparing an optically active1,4-benzodioxane derivative claimed in claim 3 wherein a catecholderivative shown by the following formula (7) ##STR12## wherein R², R³,R⁴ and R⁵ are the same defined above, is reacted with an opticallyactive 3-chloro-1,2-propanediol shown by the following formula (8)##STR13## in the presence of a base to obtain the optically active diolcompound shown by the formula (2).